Delivery system for remote treatment of an animal

ABSTRACT

A remote treatment delivery system comprising a substantially non-skin piercing dosage projectile containing a biologically active agent and a transdermal carrier.

RELATED APPLICATIONS

The present application is a U.S. National Phase Application ofInternational Application PCT/AU2007/001651, filed Oct. 31, 2007, whichclaims the benefit of U.S. Application No. 60/855,745, filed Nov. 1,2006, all of which are herein incorporated by reference in theirentirety.

TECHNICAL FIELD

The present invention relates to a remote delivery treatment system forcommercial livestock and domestic animals and wildlife management.

BACKGROUND

In practice, it is frequently difficult and costly to deliver medicinalcompounds to animals, especially if such animals are not kept inenclosures or specifically herded and contained for that purpose.Typically, during outbreaks of disease in wild animals, it is necessaryto dart diseased animals in order to deliver the required medicinalcompounds to the animals. This method of disease control and preventionis particularly stressful for the animals, and it is difficult todetermine which animals have been darted, and which animals still needto be treated. In addition, using traditional systems, it is onlypossible to dart an animal with a single dose of a medicament—if morethan one type of medicament is to be administered, the animal needs tobe darted or injected more than once, or they need to be tranquilizedindividually, and then injected with the required medicaments.

The problem of treating animals, particularly wild animals, has beencarried out in the past by development of delivery devices, such asdarts and the like, that must pierce or penetrate the skin or tissue ofthe animal. Although these devices can effectively deliver the desiredtreatment, often the animal is exposed to the potential ofpost-treatment infections at the site of delivery. An additional problemwith many of the prior art methods is that it can be, difficult todetermine or monitor which animal has been treated.

Other methods for remotely delivering agents to animals or humans caninvolve providing of aerosols in close proximity to the animal or personto be treated from a projectile that does not penetrate the skin ortissue. An example of this form of delivery can be found in US2002/0129728 in the name of Jaycor Tactical Systems. Although thissystem is particularly suitable for personnel or crowd control, itcannot deliver a defined dosage of a biologically active agent as atreatment regime to an animal. The dosage is variable and would dependon how much ‘dust or powder’ is taken up in the lungs.

WO 2005/074672 in the name of Simon Robert Trickey describes a frangiblemissile containing a treating substance that can be applied to thesurface of an animal. Unfortunately, this system has very limitedapplication as it can only provide treatment to the surface of the skin.Most veterinary medicines and chemicals, however, do not act directly onthe surface of the skin so this system does not solve the problem ofproviding an effective remote delivery system for animals.

A number of prior art treatment systems require delivery of an agent bypiercing the skin or tissue. Examples in this regard include U.S. Pat.No. 6,419,655 in the name of Gonex Inc, U.S. Pat. No. 6,584,910 in thename of David Plass, WO 00/71967 and US 2004/0089186 in the name ofRichard Brydges-Price. Each of these systems can cause injury to ananimal and are susceptible to causing post treatment infection at thesite of impact.

The present inventors have developed a system that allows the remotedelivery of a veterinary treatment to an animal without causing materialinjury to the animal.

SUMMARY OF INVENTION

In a first aspect, the present invention provides a remote treatmentdelivery system comprising:

a substantially non-skin piercing dosage projectile containing abiologically active agent and a transdermal carrier.

Preferably, the projectile comprises a frangible shell and thebiologically active agent and transdermal carrier are housed within theshell of the projectile.

In a second aspect, the present invention provides a method of remotelytreating an animal comprising:

launching a projectile of the delivery system according to the firstaspect of the present invention at an animal;

impacting the projectile on the animal to cause release of thebiologically active agent and the transdermal carrier onto the skin ofthe animal, wherein the transdermal carrier facilitates passage of thebiologically active agent through the skin to provide treatment to theanimal, wherein there is no substantial piercing of the skin by theprojectile.

In a third aspect of the invention, the present invention provides useof a delivery system according to the first aspect of the presentinvention in a method of treating an animal.

Preferably, the animal is a wildlife or game animal such as deer orother antelope species or buffalo, commercial or production livestocksuch as cattle and horses or larger bodied feral animals such as horses,buffalo wild dogs, pigs, and the like.

Preferably, the animal is treated for a condition such as disease,parasite infestation or condition, dietary deficiency, or fertility.

More preferably, the condition is parasite infection or infestation.

Preferably, the biologically active agent is present at a concentration(% v/v) of from about 0.1% to 20%. More preferably, the biologicallyactive agent is at a concentration (% v/v) of from 0.5% to 10%. Morepreferably, the biologically active agent is at a concentration (% v/v)of from 1% to 5%. It will be appreciated that the concentration of thebiologically active agent will be related to the dosage required for aparticular size of animal.

In one preferred form, the biologically active agent is apharmacological agent. Preferably, the pharmacological agent is aveterinary pharmaceutical from the established class of macrocycliclactones such as Ivermectin, eprinomectin, moxidectin, selamectin,doramectin, milbemycin, abamectin, cydectin and emamectin benzoate.

More preferably, the pharmacological agent is a parasiticide (endo andecto). Preferably, the parasiticide is avermectin and derivativesthereof including ivermectin and abamectin.

The veterinary pharmaceutical can also be selected from syntheticpyrethroids such as flumethrin, deltamethrin, cypermethrin, cyfluthrin,fenvalerate, alphacypermethrin and pyrethrin.

The veterinary pharmaceutical can also be an insect growth regulatorselected from the group consisting of yriproxifen, methoprene,cyromazine, lufenuron, diflubenzuron, fluazuron, dicyclanil andfluazuron.

The veterinary pharmaceutical can also be selected from amidines such asAmitraz. Amitraz is a triazapentadiene compound, a member of the amidineclass of antiparasitic drugs used for treating external parasites.Alternate names for Amitraz may include, but are not limited toAazdieno, Acarac, Amitraze, Avartin, Baam, Edrizan, Maitac, Mitac,Mitaban, Triatox, Triatix, Vapcozin Taktic, Triazid, Topline, Tudy,Ectodex, Garial, Danicut, Ovidrex, Acadrex, Bumetran, and Ovasyn.

The veterinary pharmaceutical can also be selected from otheranthelmintics such as fipronil, imidacloprid, rotenone, Magnesiumfluorosilicate, piperonyl butoxide, spinosyns, and benzimidazoleanthelmintics and immunomodulators (e.g. Levamisole).

In another preferred form, the biologically active agent is a healthsupplement such as a vitamin or mineral.

Examples of suitable vitamins or minerals include, but not limited to,calcium, potassium, iron, thiamine and Vitamin B12.

The biologically active agent and transdermal carrier thereof may bemade up a variety of suitable solvents or liquid combinations, such as,but not limited to, isopropyl alcohol; dipropylene glycol methyl-ether;butylated hydroxytoluene dipropylene glycol monomethyl-ether; methylenechloride; diethyl ether, ethanol, acetonitrile, ethyl acetate, benzylalcohol and a combination of natural oils.

In another preferred form, the biologically active agent is a vaccine orimmunogenic compound.

Examples of suitable vaccines include, but not limited to, PZP (PorcineZona Pelucida), Foot and Mouth, Bovine Tuberculosis, Tuberculosis, andother compatible live or attenuated vaccines known to the art to exposea treated animal to pathogenic organisms in a manner that provokes animmune response.

In this preferred form, the composition may include one or moreadjuvants to assist in the efficacy of the vaccine. Suitable adjuvantswould be readily known to a person skilled in the art. It will beappreciated that the adjuvant may also act as a transdermal carrier toassist in the movement of the biologically active agent.

The biologically active agent may include drugs such as contraceptives,analgesics, anti-inflammatories, vasodilators, bronchodilators,diuretics, anti-histamines, tranquilizers, anti-fungals, vitamins,muscle relaxants, and anti-virals, anti-parasitic compositions,anthelmintics, acaricides, insecticides, and the like. Alternatively, oradditionally, the biologically active agent may include a hormone suchas a progesterone, estrogen, testosterone, derivatives thereof, and/orcombinations of such hormones. The biologically active agent may alsoinclude protein-based agents, such as crude or purified cell lysates,sub-unit vaccines, protein-based antigen display systems, antigens,peptides, oligopeptides, or polypeptides that are absorbable through theskin of the animal when used in combination with a transdermal carrier,for example proteinaceous or glycoprotein-derived contraceptives, suchas a zona pellucida based contraceptive, e.g. the Porcine Zona Pellucida(PZP) contraceptive.

The biologically active agent may include any suitable antigen to whichan immune response is desired in an animal. Examples include, but notlimited to, Foot and Mouth Disease, tuberculosis, Vibrio cholera choleratoxin, tetanus toxide, bacterial ADP ribosylating exotoxin (bARE),Escherichia coli heat-labile enterotoxin, and mutants and derivativesthereof, and may include a mixture of any such transcutaneousimmunization compositions.

The biologically active agent and transdermal carrier thereof may bemade up in any suitable solvent or liquid, such as, but not limited to,isopropyl alcohol; dipropylene glycol methyl-ether; butylatedhydroxytoluene dipropylene glycol monomethyl-ether; methylene chloride;diethyl ether, ethanol, acetonitrile, ethyl acetate, benzyl alcohol anda combination of natural oils.

In use the transdermal carrier facilitates passage of the biologicallyactive agent through the skin of an animal in need of treatment. In thecase of a vaccine, the transdermal carrier may also act as an adjuvantor facilitate the passage of an adjuvant if used.

It is to be understood that any suitable transdermal carrier or solventwhich facilitates transdermal absorption of the active ingredient may beused. Typically, the transdermal carrier includes carriers such asisopropyl alcohol, dipropylene glycol methyl-ether, butylatedhydroxytoluene dipropylene glycol monomethyl-ether, 1-methoxy 2-propanol(glysolv PM/Icinol PM), Ethylene glycol monobutylether (butylglyxolv/butyl icinol), Butyl di glysolv (butyl-icinol), Transcutol,propylene glycol (PG), N-methyl-2 pyrrolidone (NMP), methylene chloride,diethyl ether, ethanol, acetonitrile, ethyl acetate, benzyl alcohol anda combination of natural oils; ethylene glycol, propylene glycol,dimethyl polysiloxane (DMPX), oleic acid, caprylic acid, 1-octanol,ethanol (denatured or anhydrous), liposomal compositions, suitable plantoils, such as Aloe vera derivatives or sesame seed oil or derivativesthereof, acrylic polymers, rubber-based polymers, polysiloxane-basedpolymers, polyvinylpyrrolidone-based polymers, dimethylsulfoxide (DMSO),dimethylformamide (DMF), lecithin, Transfersomes® (IDEA AG).Transfersomes® are artificial vesicles designed to mimic a cell vesicleand deluver drugs or genetic material into a cell. The bounding membraneof a Transfersomes® is more flexible than that of a liposome, allowingit to deform and pass through openings in a barrier, such as the skin,whose diameters are much smaller than the average vesicle size. ATransfersomes® is a bi-component, most often vesicular, aggregate. Themain functional characteristic of the aggregate is the extremeflexibility and permeability of its bilayer-like membrane coating. Itsbasis is the interdependency of local membrane shape and composition,which makes the bilayer self-regulating and self-optimising. The bilayeris thus capable of stress adaptation, via local and reversible bilayercomponent demixing. These characteristics make Transfersomes® into adevice suitable for non-invasive and targeted drug delivery, inter aliaacross intact skin.

Additional transdermal carriers include, but are not limited to,ethosomes, azone, castor oil derivatives, such as ethoxylated castoroil, jojoba oil derivatives, corn oil derivatives, emu oil derivatives,or any other suitable transdermal or transcutaneous carrier or carriercomposition.

Preferably, the transdermal carrier is propylene glycol, DMSO, alcoholor a more penetrant adjuvant known to the art.

The delivery system may further comprise a marker. The marker may be anon-toxic, physiologically acceptable dye, sufficient to mark the skin,coat or fur of an animal for a period of about 1 hour to about 72 hours,preferably about 24 to 48 hours. The marker may be a pharmaceutical,food, or cosmetic colorant, pigment, or dye. Examples of suitablemarking components include liquid dyes, powder dyes, water soluble dyes,infra-red dyes, ultraviolet dyes, or dyes that glow in the dark (e.g.,chemiluminescent dye's or phosphorescent dyes). It is to be understoodthat the dyes may be selected so as not to impair or interfere with theaction or efficacy of the biologically active agent or the transdermalcarrier.

The marker may be fluorescent, rendering animals which have been markedor treated under low-light conditions easily visible. The marker and/orsolution may also contain a radioactive or other suitable trackingcomponent.

Typically, the projectile is shot from a launching device such as a gunpressure or gas activated launcher or the like. Examples of potentiallysuitable launching devices may be based on similar gas dischargetechnologies utilized in current dart guns, air guns, crowd control gunsand paintball markers currently in production and used in theveterinary, security, law enforcement, hunting, and recreationalshooting or paintball industry.

The projectile is adapted to deliver the biologically active agent tothe animal substantially without piercing the skin of the animal.Accordingly, the biologically active agent may be transported (with theaid of transdermal solvents) through the skin following rupturing of theprojectile upon contact with the animal, penetration of the biologicallyactive agent being effected by the transdermal carrier contained withinthe projectile.

The shell of the projectile may be made of any suitable encapsulatingmaterial, such as, for example, gelatine, linear polymers, orpolystyrene derivatives, thin-walled plastics materials, hydrophiliccolloidal materials such as, gelatin, albumin, gum arabic, alginate,casein, agar or pectins, or combinations thereof, or synthetic organiccompounds such as, but not limited to, polystyrene, polypropylene,polyethylene, polycarbonate, polyamide, polysulfane, polyvinylchloride,resinous compounds such as fibreglass or Perspex derivatives, orcombinations thereof.

Preferably, the frangible shell of the projectile is made of softgelatine, glycerol and/or sorbitol and combinations thereof.

The biologically active agent and transdermal carrier may beencapsulated in one or more encapsulating or coating agents in order tomore effectively control the delivery rate of the biologically activeagent and transdermal carrier to the animal. The encapsulating orcoating agent may be chosen such that it regulates the release of thebiologically active agent once it has been absorbed into the bloodstream or lymphatic system of the animal.

The projectiles may be launched with a single trigger action from aprojectile launcher. The projectile launcher may include a selector forselecting the number of projectiles to be launched with a single triggeraction. Alternatively, the projectiles may be delivered using asemi-automatic trigger action.

The projectiles, when used to deliver multiple biologically activeagents or doses, may include biologically active agents which aresimilar or differing in composition, efficacy, or pharmaceutical action.Accordingly, it is to be understood that the dose administered to ananimal may be controlled by selecting the number and type of dosageforms or projectiles to be launched at an animal. In this way, a usercan easily adjust the dose required for correctly dosing the animal, bycompensating for the size and weight of an animal, and tailor dosingregimens.

It will be appreciated that the treatment may be prophylactic.

The projectile launcher may include velocity selection means operable toselect the velocity at which the projectile is launched. For example thevelocity selection means may include pressure-regulating means operableto select the pressure at which the pressurized fluid is released.

The launching propellant may be a pressurized fluid, such as gas or air.

The present invention has the following advantages:

-   -   I. a bio mechanical system for the remote delivery of treatment        to an animal from a safe or remote distance without need for        immediate proximity to the animal    -   II. can include use of a gas propelled launcher and a soft        dosage projectile projectile containing a liquid solution with        substantially no solid matter likely to cause skin rupture or        other impact site wound    -   III. enabling the topical administration of a biologically        active agent of a suitably solubilised pharmacological agent or        compound    -   IV. can include a marking compound    -   V. impact of projectile on an animal leads to transdermal        absorption of a desired amount or dose of a biologically active        agent so as to produce the required therapeutic, blood or health        levels in the animal    -   VI. effective to treat by systemic action a disease or parasite        infestation condition of the animal either at pasture or in its        natural habitat and thereby avoiding:        -   unnecessary stress and danger to the animal and/or its            handlers        -   the need for capture, herding or containment and associated            risk of injury        -   infliction of treatment site wounding and associated risk of            secondary infection.

Throughout this specification, unless the context requires otherwise,the word “comprise”, or variations such as “comprises” or “comprising”,will be understood to imply the inclusion of a stated element, integeror step, or group of elements, integers or steps, but not the exclusionof any other element, integer or step, or group of elements, integers orsteps.

In order that the present invention may be more clearly understood,preferred embodiments will be described with reference to the followingdrawings and examples.

MODE(S) FOR CARRYING OUT THE INVENTION Definitions

The term “animal” is to be accorded its widest meaning, and may includemammalian species, marsupials, and bird species.

The term “transdermal” as used herein is to be accorded its widestmeaning, and may include transcutaneous administration.

The term “biologically active agent” (and its equivalents “medicament”,“agent”, “drug”, “active agent” and “pharmaceutical”) is intended tohave the broadest meaning and includes at least one of any therapeutic,prophylactic, vaccine, antigenic, pharmacological, anti infective(antibiotic or antiseptic) or physiologically active substance, which isdeliverable to an animal to produce a desired, usually beneficial,effect. More specifically, any suitable biologically active agent thatis capable of producing a pharmacological response, localized orsystemic, irrespective of whether therapeutic, diagnostic, orprophylactic in nature, is within the contemplation of the invention. Itshould be rioted that the biologically active agents can be usedsingularly or in combinations and mixtures as required.

Steroidal hormones can be used in the present invention and may include,in certain embodiments, but not limited to, estrogenically effectivesteroid hormones such as colpormon, conjugated estrogens, estradiol andestradiol esters.

Anti-infectives and mineral and vitamin supplements as specified, otherbiologically active agents or specific parasiticide and/or anthelminticdrugs which may be employed more specifically in embodiments of theinvention include, but are not limited to:

Macrocyclic Lactones including the avermectins and milbemycins, forexample Ivermectin, eprinomectin, moxidectin, selamectin, doramectin,milbemycin, abamectin, cydectin and emamectin benzoate.

Synthetic pyrethroids such as flumethrin, deltamethrin, cypermethrin,cyfluthrin, fenvalerate, alphacypermethrin and pyrethrin.

Insect Growth Regulators such as yriproxifen, methoprene, cyromazine,lufenuron, diflubenzuron, fluazuron, dicyclanil and fluazuron.

Other anthelmintics such as fipronil, imidacloprid, rotenone, Mgfluorosilicate, piperonyl butoxide, spinosyns and other suitablebenzimidazole anthelmintics and immunomodulators (e.g. Levamisole).

In one embodiment, the biologically active agent is a transdermalimmunization composition, including Vibrio cholera cholera toxin,tetanus toxoidtoxoid, bacterial ADP ribosylating exotoxin (bARE), Footand Mouth Disease antigens, tuberculosis antigens, and/or Escherichiacoli heat-labile enterotoxin, and/or mutants and derivatives thereof. Italso includes a mixture of any such transdermal immunizationcompositions and/or other medicaments. The transdermal immunizationcompositions or mixtures thereof may be made up in any suitable solventor liquid, such as, but not limited to, water or alcohol. Thetransdermal immunization compositions can further serve as transdermalcarriers in their own right, in that they facilitate the dermalpenetration of other biologically active agents, compositions,polypeptides, oligopeptides, or peptide fragments.

Steroidal hormones can be used in the present invention and may include,in certain embodiments, estrogenically effective steroid hormones suchas colpormon, conjugated estrogens, estradiol and estradiol esters (e.g.acetate, benzoate, cypionate, dipropionate diacetate, enanthate,undecylate and valerate), estriol, estrone, ethinyl estradiol,equilenin, equilin, mestranol, moxestrol, mytatrienediol, quinestradioland quinestrol; progestagenically effective steroid hormones such asallylestrenol, anagestone, chlormadinone acetate, delmadinone acetate,demegestone, desogestrel, 3-keto desogestrel, dimethisterone,dydrogesterone, ethinylestrenol, ethisterone, ethynodiol (anddiacetate), fluorogestone acetate, gestodene, gestonorone caproate,haloprogesterone, (17-hydroxy- and 17-acetate-)16-methylene-progesterone, 17α-hydroxyprogesterone (acetate andcaproate), levonorgestrel, lynestrenol, medrogestone,medroxyprogesterone (and acetate), megestrol acetate, melengestrol,norethindrone (acetate and enanthate), norethisterone, norethynodrel,norgesterone, norgestimate, norgestrel, norgestrienone,19-norprogesterone, norvinisterone, pentagestrone, progesterone,promegestone, quingestrone and trengestone; androgenically effectivesteroid hormones such as aldosterone, androsterone, boldenone,cloxotestosterone, dehydroepiandrosterone, fluoxymesterone, mestanolone,mesterolone, methandrostenolone, methyltestosterone,17α-methyltestosterone, 17α-methyltestosterone 3-cyclopentyl enol ether,norethandrolone, normethandrone, oxandrolone, oxymesterone,oxymetholone, prasterone, stanolone, stanozolol, testosterone (acetate,enanthate, isobutyrate, propionate and undecanoate),testosterone-17-chloral hemi-acetal, testosterone-17β-cypionate, ortiomesterone.

Other biologically active agents or specific drugs which may be employedin embodiments of the invention include, but are not limited to:

Anaesthetic agents and analgesics, such as benzocaine, bupivicaine,capsaicin, cocaine, dibucaine, dyclonine, etidocaine, lidocaine,mepivacaine, prilocaine, procaine and tetracaine, acetaminophen,acetylsalicylic acid, buprenorphine, codeine, fentanyl, hydromorphone,lisuride, salicylic acid derivatives, sufentanil and sumatriptan.

Antibacterial or antibiotic agents such as aminoglycosides, δ-lactams,cephamycins, macrolides, penicillins, polypeptides and tetracyclines.

Anthelmintic, anti-trematodal, anticestodal, oranti-parasitic/parasiticidal agents such as albendazole, levamisole,mebendazole, pyrantel, praziquantel, moxidectin, ivermectin,oxamniquine, metrifonate, piperazine, thiabendazole, tiabendazole,diethylcarbamazine, pyrantel, niclosamide, doramectin, eprinomectin,morantel, oxfendazole, dichlorvos, chlorsulon and selamectin.

Acaricidal agents including antibiotic acaricides, nikkomycins,thuringiensin, macrocyclic lactones, acaricides, tetranactin,avermectin, acaricides, abamectin, doramectin, eprinomectin, ivermectin,selamectin, milbemycin, acaricides, milbemectin, milbemycin oxime,moxidectin, bridged diphenyl acaricides, azobenzene, benzoximate, benzylbenzoate, bromopropylate, chlorbenside, chlorfenethol, chlorfenson,chlorfensulphide, chlorobenzilate, chloropropylate, cyflumetofen,dicofol, diphenyl sulfone, dofenapyn, fenson, fentrifanil, fluorbenside,proclonol, tetradifon, tetrasul, carbamate acaricides, benomyl,carbanolate, carbaryl, carbofuran, methiocarb, metolcarb, promacyl,propoxur, oxime carbamate caricides, aldicarb, butocarboxim, oxamyl,thiocarboxime, thiofanox, dinitrophenol acaricides, binapacryl, dinex,dinobuton, dinocap, dinocap-6, dinocton, dinopenton, dinosulfon,dinoterbon, DNOC, formamidine acaricides, amidines, amitraz,chlordimeform, chloromebuform, formetanate, formparanate, mite growthregulators, clofentezine, diflovidazin, dofenapyn, fluazuron,flubenzimine, flucycloxuron, flufenoxuron, hexythiazox, organochlorineacaricides, bromocyclen, camphechlor, dienochlor, endosulfan, lindane,organophosphorus acaricides, organophosphate acaricides,chlorfenvinphos, crotoxyphos, dichlorvos, heptenophos, mevinphos,monocrotophos, TEPP, tetrachlorvinphos, organothiophosphate acaricides,amidithion, amiton, azinphos-ethyl, azinphos-methyl, azothoate,benoxafos, bromophos, bromophos-ethyl, carbophenothion, chlorpyrifos,chlorthiophos, coumaphos, cyanthoate, demeton, demeton-O, demeton-S,demeton-methyl, demeton-O-methyl, demeton-5-methyl,demeton-5-methylsulphon, dialifos, diazinon, dimethoate, dioxathion,disulfoton, endothion, ethion, ethoate-methyl, formothion, malathion,mecarbam, methacrifos, omethoate, oxydeprofos, oxydisulfoton, parathion,phenkapton, phorate, phosalone, phosmet, phoxim, pirimiphos-methyl,prothidathion, prothoate, pyrimitate, quinalphos, quintiofos, sophamide,sulfotep, thiometon, triazophos, trifenofos, vamidothion, phosphonateacaricides, trichlorfon, phosphoramidothioate acaricides, isocarbophos,methamidophos, propetamphos, phosphorodiamide caricides, dimefox,mipafox, schradan, organotin acaricides, azocyclotin, cyhexatin,fenbutatin, phenylsulfamide acaricides, dichlofluanid, phthalimideacaricides, dialifos, phosmet, pyrazole acaricides, acetoprole,fipronil, tebufenpyrad, vaniliprole, pyrethroid acaricides, pyrethroidester caricides, acrinathrin, bifenthrin, cyhalothrin, cypermethrin,alpha-ypermethrin, fenpropathrin, fenvalerate, flucythrinate,flumethrin, fluvalinate, tau-fluvalinate, permethrin, pyrethroid etheracaricides, halfenprox, pyrimidinamine acaricides, pyrimidifen, pyrroleacaricides, chlorfenapyr, quinoxaline acaricides, chinomethionat,thioquinox, sulfite ester caricides, propargite, tetrazine acaricides,clofentezine, diflovidazin, tetronic acid acaricides, spirodiclofen,thiocarbamate acaricides, fenothiocarb, thiourea acaricides,chloromethiuron, diafenthiuron, unclassified acaricides, acequinocyl,amidoflumet, arsenous oxide, bifenazate, closantel, crotamiton,disulfiram, etoxazole, fenazaflor, fenazaquin, fenpyroximate,fluacrypyrim, fluenetil, mesulfen, MNAF, nifluridide, pyridaben,sulfiram, sulfluramid, sulfur triarathene.

Anti-fungal agents such as clortrimazole, ketoconazole, miconazole,nystatin and triacetin.

Antihistamine agents such as tricyclics such as ahistan, etymemazine,fenethazine, n-hydroxyethylpromethazine chloride, isopromethazine,mequitazine, promethazine, pyrathiazine, and thiazinamium methyl

Anti-inflammatory and/or corticoid agents such as beclomethasone,betamethasone (and acetate, diproprionate and valerate), corticosterone,cortisone, deoxycortocosterone (and acetate), dexamethasone, diclofenac,fenoprofen, flucinolone (and acetonide), fludrocortisone, fluocinonide,flunisolide, fluradrenolide, flurbiprofen, halcinonide, hydrocortisone(and acetate), ibuprofen, ibuproxam, indoprofen, ketoprofen, ketorolac,naproxen, oxametacine, oxyphenbutazone, piroxicam, prednisolone,prednisone, suprofen and triamcinolone (and acetonide).

Antiviral agents such as acyclovir, rimantadine and vidarabine.

Anxiolytic agents such as azapirones such as buspirone and ipsapirone,benzodiazepines such as alprazolam, chlordiazepoxide, clonazepam,clorazepate, diazepam, flurazepam, halazepam, lorazepam, oxazepam,oxazolam, prazepam and triazolam.

β-Adrenergic agonist agents such as albuterol, carbuterol, fenoterol,metaproterenol, mirtazapine, rimiterol, quinterenol, salmefamol,soterenol, tratoquinol, terbutaline and terbuterol.

Bronchodilators such as ephedrine derivatives including

Anti-allergy agents such as amlexanox, astemizole, azelastine, cromolyn,fenpiprane, ibudilast, nedocromil, oxatomide, pentigetide, repirinast,tranilast and traxanox.

Cardioactive agents such as atenolol, benzydroflumethiazide,bendroflumethiazide, calcitonin, captopril, chlorothiazide, clonidine,clopamide, dobutamine, dopamine, diltiazem, enalapril, enalaprilat,gallopamil, indomethacin, isosorbide (dinitrate and mononitrate),monoxidil, nicardipine, nifedipine, nitroglycerin, papaverine, prazosin,procainamide, propranolol, prostaglandin E₁ and E₂, quinidine

Central Nervous System stimulants and agents such as dextroamphetamine,methylphenidate, and nicotine.

Cholinergic agents such as acetylcholine, arecoline, bethanechol,carbachol, choline, methacoline, muscarine and pilocarpine.

Anti-cholinergic agents such as atropine, eucatropine and procyclidine.Anti-emetic agents such as acetylleucine monoethanolamine, alizapride,benzquinamide, bietanautine, bromopride, buclizine, chlorpromazine,clebopride, cyclizine, dimenhydrinate, dipheniodol, domperidone,granisetron, meclizine, methalltal, metoclopramide, metopimazine,nabilone, ondansteron, oxypendyl, pipamazine, piprinhydrinate,prochlorperazine, scopolamine, tetrahydrocannabinols, thiethylperazine,thioproperzaine, trimethobenzamide and tropisetron.

Muscle relaxants such as Baclofen.

The term, “therapeutically effective” as used herein means an amount ofa biologically active agent that is sufficient to achieve a desiredlocal or systemic effect or result, such as to prevent, cure, mitigateor treat a disease or condition as required.

The amounts of the biologically active agent to be used in a projectilemay be determined by methods known to persons skilled in the field ofthe invention. Amounts typically range from about 0.05 mg to about20,000 mg, and preferably from about 0.1 mg to about 1,000 mg, dependingon the biologically active agent, the disease to be treated, the animalspecies, the size of the animal and the transdermal carrier used. Incertain embodiments of the invention, the biologically active agents maybe included in a range from about 0.1 to about 500 mg per mammal per 50kg body weight.

The term “transdermal carrier” or “transdermal carrier composition” asused herein refers to any material known in the art as being suitablefor transdermal agent delivery administration, and includes anypolymeric material into which an active agent may be solubilised incombination or admixture with the other ingredients of the composition.The term may also include enhancers, solvents, co-solvents, carriers andother types of additives useful for facilitating transdermal drugdelivery, or adhesives for ensuring adhesion of the contents of theprojectile to the skin, coat or fur of a target animal.

The transdermal carrier is typically used in an amount of about 1% toabout 95%, and preferably from about 10% to about 75%, by weight basedon the weight of the total carrier composition.

The transdermal carrier composition of the present invention can alsocontain one or more solvents and/or co-solvents known in the art.

Suitable solvents and co-solvents include volatile substances orcompositions such as alcohols, aromatic hydrocarbons such as benzenederivatives, lower molecular weight alkanes and cycloalkanes, alkanoicacid esters, polyhydric alcohols, which include glycols, triols and,polyols such as ethylene glycol, diethylene glycol, propylene glycol,dipropylene glycol, trimethylene glycol, butylene glycol, polyethyleneglycol, hexylene glycol, polyoxethylene, glycerin, trimethylpropane,sorbitol, polyvinylpyrrolidone, glycol ethers such as ethylene glycolmonoethyl ether, glycol esters, glycol ether esters such as ethyleneglycol monoethyl ether acetate and ethylene glycol diacetate; saturatedand unsaturated fatty acids, mineral oil, silicone fluid, lecithin,retinol derivatives and the like, and ethers, esters and alcohols offatty acids. or combinations and mixtures thereof.

Although the exact amount of solvents and co-solvents that may be usedin the carrier composition depends on the nature and amount of the otheringredients, such amount typically ranges from about 0.1% to about 50%,and preferably from about 0.1% to about 30% by weight, and morepreferably from about 1% to about 20%, by weight based on the dry weightof the total carrier composition.

The transdermal carrier is typically selected so that it may be readilyabsorbable by the skin of an animal without causing undue itching,irritation, or toxic effects to the animal. Selection of the transdermalcarrier will also depend on the biologically active agent to bedelivered to an animal and also the type of animal to be treated, or theintended delivery site on an animal. Thus, the transdermal carriercomposition 16 may be selected to suit the charge, size, hydrophobicity,hydrophilicity, amphipathicity, pI, pH, decay rate, or other relevantcriteria of the biologically active agent to be carried transdermally,while also being readily absorbable through the skin of an animal.

Typically, the transdermal carrier includes compounds such as isopropylalcohol, dipropylene glycol methyl-ether, butylated hydroxytoluenedipropylene glycol monomethyl-ether, methylene chloride, 1-methoxy2-propanol (glysolv PM/Icinol PM), Ethylene glycol monobutylether (butylglyxolv/butyl icinol), Butyl di glysolv (butyl-icinol), Transcutol,propylene glycol (PG), N-methyl-2 pyrrolidone (NMP), diethyl ether,ethanol, acetonitrile, ethyl acetate, benzyl alcohol and a combinationof natural oils. ethylene glycol, propylene glycol, dimethylpolysiloxane (DMPX), oleic acid, caprylic acid, 1-octanol, ethanol(denatured or anhydrous), liposomal compositions, suitable plant oils,such as Aloe vera derivatives or sesame seed oil or derivatives thereof,acrylic polymers, rubber-based polymers, polysiloxane-based polymers,polyvinylpyrrolidone-based polymers, dimethylsulfoxide (DMSO),dimethylformamide (DMF), lecithin, Transfersomes®, ethosomes, azone,castor oil derivatives, such as ethoxylated castor oil, jojoba oilderivatives, corn oil derivatives, emu oil derivatives, or othersuitable carriers.

In certain embodiments of the invention, an enhancer is incorporatedinto the carrier composition. The term “enhancers” as used herein refersto substances used to increase permeability and/or accelerate thedelivery of an active agent through the skin of an animal, and includemonohydric alcohols such as ethyl, isopropyl, butyl and benzyl alcohols;or dihydric alcohols such as ethylene glycol, diethylene glycol, orpropylene glycol dipropylene glycol and trimethylene glycol; orpolyhydric alcohols such as glycerin, sorbitol and polyethylene glycol,which enhance drug solubility; polyethylene glycol ethers of aliphaticalcohols (such as cetyl, lauryl, oleyl and stearly) includingpolyoxyethylene-4-lauryl ether, polyoxyethylene-2-oleyl ether andpolyoxyethylene-10-oleyl ether; vegetable, animal and fish fats and oilssuch as cotton seed, corn, safflower, olive and castor oils, squalene,and lanolin; fatty acid esters such as propyl oleate, decyl oleate,isopropyl palmitate, glycol palmitate, glycol laurate, dodecylmyristate, isopropyl myristate and glycol stearate which enhance drugdiffusibility; fatty acid alcohols such as oleyl alcohol and itsderivatives; fatty acid amides such as oleamide and its derivatives;urea and urea derivatives such as allantoin which affect the ability ofkeratin to retain moisture; polar solvents such asdimethyldecylphosphoxide, methyloctylsulfoxide, dimethyllaurylamide,dodecylpyrrolidone, isosorbitol, dimethylacetonide, dimethylsulfoxide,decylmethylsulfoxide and dimethylformamide; salicylic acid; benzylnicotinate; or higher molecular weight aliphatic surfactants such aslauryl sulfate salts, esters of sorbitol and sorbitol anhydride such aspolysorbate. Other suitable enhancers include oleic and linoleic acids,triacetin, ascorbic acid, panthenol, butylated hydroxytoluene,tocopherol, tocopherol acetate, tocopheryl linoleate.

If enhancers are incorporated into the carrier composition, the amounttypically ranges up to about 35%, and preferably from about 0.05% toabout 20%, by weight based on the dry weight of the total carriercomposition.

Use

Most current treatment methods require immediate proximity to theanimal. In contrast, the present invention can provide remote deliveryfrom a safe distance and is the only administration option which avoidscapture, sedation or mustering/herding of animals. The incidence ofsecondary infection from needle site or treatment wound is particularlysignificant in the case of wild animal species (exposed to the elements)and is a material problem in the industry. Equally, the incidence ofinjury to animals and handlers when stock such as cattle are mustered,yarded and driven through a crush for individual dipping/treatmentapplication can be a problem.

Prior art remote, projectile based delivery methods which do notdeliberately pierce the skin (dart, syringe, silicon implant) areineffective. The present inventors have developed a system for remotedelivery/administration that can treat an animal systemically. Theparasite treatments formulated only for dip or spray application must beadministered to substantially the whole of the animals skin toeffectively treat external parasites.

The reliable delivery of a full dosage is fundamentally important,particularly with parasiticides. Under dosing leads to mutation andrapid resistance build up. In terms of efficacy considerations, anytreatment method which ensures delivery of an effective dose willtherefore be favoured over those with arbitrary dosage characteristics.The present invention is adaptable for reliable dosage control matchedonly by injection.

Administration of biologically active agents by food/water additive,sprays etc is notoriously arbitrary. Individual dosage accuracy also hascost and environmental implications. Splash and spillage from diptreatment involves additional ingredient lost to wastage. It isgenerally unlawful to use or apply a pharmaceutical agent withoutregulatory license or authority. The product and any apparatus used todeliver it must meet the required standards of safety, efficacy andtolerance.

Most (if not all) of the current art methods can involve impact siteinjury or skin rupture of a scale unlikely to be acceptable toveterinary practitioners and/or the licensing authorities on both animalwelfare and potential for secondary infection grounds.

The projectile according to the present invention does not cause ruptureof the skin but the impact may cause mild bruising. Any bruising causesthe local, blood vessels to dilate and rise to the under surface of theskin at the affected area. This increased blood flow at the deliverysite potentially enhances the speed and extent of take up of thebiologically active agent. This can lead to an increased efficacy resultover a similar dosage of the same treatment compound applied topicallyby proximate pour on or spot on methods. Animal trial results haveindicated that no unacceptable tissue damage is caused by the projectilehitting the skin and the impact site is fully normalised within daysafter treatment.

The present invention relates to the treatment of animals, especiallywild animals or animals which may be free-ranging and not in captivity.Such animals are difficult or cumbersome to capture and treat usingconventional methods. Most current methods for treating wild animals arehighly stressful to the animals, and include darting the animals,chasing them into catch-nets or enclosures, or sedating them prior toadministering treatment. The prior art methods are also dangerous to thepersons administering such treatments, as darts have to be usedcontaining potentially hazardous drugs including highly toxic morphinerelated drugs such as etorphine hydrochloride, and the risk ofneedle-stick or injury is high when attempting to dart as many animalsas possible. Furthermore, in current methods it is often difficult forthe person administering the treatment to determine which animals havebeen treated and which animals are still to be treated. This isespecially difficult when treating the animals from an elevated area orfrom a helicopter.

The present invention is not limited to wildlife only, but also findsapplication in the treatment of commercial livestock, domestic animalsand companion animals. In the case of cattle, use of the invention asdescribed herein considerably lowers the stress levels of the animals,as compared to conventional dipping or inoculation techniques andreduces treatment process costs.

Typically, projectiles are made from a substance such as, but notlimited to, hydrophilic colloidal materials such as, gelatin, albumin,gum arabic, alginate, casein, agar or pectins, or combinations thereof.The projectile can also be made from a synthetic organic compound suchas, but not limited to, polystyrene, polypropylene, polyethylene,polycarbonate, polyamide, polysulfane, polyvinylchloride, resinouscompounds such as fibreglass or Perspex derivatives, or combinationsthereof.

The projectile includes a biologically active agent, a transdermalcarrier, and optionally a dye or marker. The biologically active agentcan be encapsulated in a controlled-release coating prior to inclusionin the projectile thereby allowing the controlled release of thebiologically active agent within an animal to be treated animal, once ithas passed transdermally into the blood or lymphatic system of theanimal. The controlled-release coating may be selected from controlledrelease compositions known in the field.

Although it is within the contemplation of the invention that externallyadministrable biologically active agents may also be included within theprojectile, the invention is especially suited to delivering systemictreatments for the treatment of endoparasites or ectoparasites toanimals. The treatments may, accordingly, be absorbed by and distributedthrough the blood or lymphatic system of an animal, once it has beenabsorbed though the skin of an animal. It is thus an aim of the presentinvention that the biologically active agents are deliverable to animalsby absorption through the skin, and not by a piercing element or needle,so that animals may be treated systemically, substantially withoutinsulting the skin of the animal.

Avermectin and its derivatives are examples of biologically activeagents within the contemplation of this invention that constitute afine, solid powder in their pure form. It is accepted within the artthat external administration of such agents in their natural pure formhas no material therapeutic effect—prior toxicity studies haveestablished that primate skin types in contact with pure ivermectinabsorb less than 1% of the active agent into the bloodstream. Thesuccessful development of externally administered ‘pour on’ and ‘spoton’ products has demonstrated that therapeutically effective blooduptake levels in animals can only be achieved through externaladministration of the avermectins in solubilised form. The appropriatesolvents known in the art also act as transdermal carriers to enableeffective therapeutic amounts of the active pharmaceutical ingredient tobe absorbed through the skin and into the bloodstream. The applicantshave commissioned specific field and clinical veterinary trials havebeen carried out to confirm that the administration of non-solubilisedivermectin is equally ineffective to treat animal disease whenadministered externally by the methods contemplated by the presentinvention—the results are reported in the Trial Data section below.

The projectile may also include a pharmaceutically acceptable dye ormarker composition. The dye or marker is released onto the skin of ananimal when the projectile ruptures upon impact with the animal. The dyeor marker may be brightly coloured to allow a person administering thetreatment to see readily which animals have been treated, and where theprojectile has ruptured on the animal. The dye or marker is preferablynon-permanent in nature, so that it may no longer be visible on treatedanimals within a day or two. Preferably, in wildlife management the dyeis non-permanent so as not to detract from the aesthetics of gamewatching.

In one embodiment of the present invention, the dye is a fluorescent dyesuch that animals, especially nocturnal animals, may be marked ortreated at night time. The dyes used in rupturable projectiles currentlyused in paintball games are generally considered suitable for use in theprojectiles of the invention (and are available in a wide variety ofcolours) provided they do not interfere with the biologically activeagent or the transdermal carrier included in the projectile.

It is to be appreciated that the viscosity of the projectile contentsshould be such that the contents do not run off the skin, fur or coat ofthe animal prematurely before treatment has occurred. Accordingly, theprojectile may also include a thickening agent, such as a starch-likecompound, inert polymer, gel, or an oil-based composition such as sesameseed oil, if required.

The biologically active agent or agents contained in the projectile canbe in different forms and/or concentrations, depending on theformulation, the carrying capacity, and solubility, and releasecharacteristics desired, for example as neutral molecules, components ofmolecular complexes, and pharmaceutically acceptable salts, free acidsor bases, or quaternary, salts thereof. Simple derivatives of thebiologically active agents mentioned herein, such as pharmaceuticallyacceptable ethers, esters, amides and the like which have desirableretention and release characteristics in vivo, and enzymes, pro-activeforms, pro-drugs and the like, can also be employed as required.

The amount of biologically active agent to be complexed with thetransdermal carrier will vary depending on the particular active agent,the desired therapeutic effect, and the time span for which thebiologically active agent is to be therapeutically effective. Normally,the amount of biologically active agent in the transdermal system canvary from about 0.1% to about 50%, or even from about 0.1% to about 30%by weight based on the dry weight of the total carrier composition.Persons skilled in the field of the invention will be able to determinethe adequate amounts required for each application, as required. Forexamples, for lower dose concentrations, such as with steroidal hormonesor corticosteroids, the preferred amount need only be from about 0.1% toabout 10%.

It is to be appreciated that the order of steps, the amounts of theingredients, and the amount and time of mixing may be important processvariables which will depend on the specific polymers, marking dyes,biologically active agents, solvents and/or co-solvents, enhancers,additives and/or excipients used in the composition.

The examples provided herein are not to be interpreted as being anexhaustive list of possible integers or embodiments of the invention,and serve merely to illustrate the invention.

The system may include a projectile launcher in the form of an airlauncher to be used in combination with the projectile of the inventionin treating animals. The projectile launcher can include a magazine orreservoir for accepting a plurality of projectiles. Administering adesired biologically active agent to a target animal is accomplished bya person or user aiming the launcher containing one or more projectilesat the animal, and launching a projectile at the animal with a velocitysufficient to rupture the projectile upon impact with the animal. Thisallows the contents of the projectile to be splattered onto the skin ofthe animal, allowing the biologically active agent to be absorbedthrough the skin of the animal via the transdermal carrier.

The impact of the projectile against the animal also serves to splatterthe marker dye, if present, onto the skin of the animal, therebyenabling the user administering the treatment to readily discern whetherthe animal has been treated, where the site of impact was on the animal(if the site of impact is important to the efficacy and absorption of aspecific biologically active agent) and whether the projectile hasruptured successfully or not.

While the projectile of the invention need not be compartmentalized inorder to separate the biologically active agent, transdermal carrier,and/or dye composition from one another inside the projectile, it iswithin the contemplation of the invention that the projectile includesone or more interstitial compartments so as to keep one or more of thecomponents of the projectile from one or more of the other componentsand only allowing them to mix upon impact with the animal.

The projectiles may have sufficient volume to contain a unit dosage fora certain disease for an animal. The dosage is typically calculated tocorrespond to a certain minimum weight of animal to which a biologicallyactive agent is to be administered. If larger animals need to betreated, the number of projectiles launched at the animal may beincreased accordingly. Alternatively, a single projectile dosage for allanimal weights may be preserved by alteration of the formulationconcentration of the active pharmaceutical agent.

For example, in order to treat a young impala weighing, say, 50 kg, asingle projectile containing a unit dosage may be enough. However, inorder to provide a sufficiently efficacious dose to a larger impalaestimated to weigh, say, 100 kg, two projectiles may be required.

The launcher can have a selector button which allows one to pre-selectthe number of projectiles to be launched at the single pull of a triggerof the launcher, thereby allowing larger animals to be treated with thecorrect dose required, merely by selecting the number of projectiles tobe launched simultaneously. This has the advantage that the animal doesnot have a chance to escape following the first firing of the launcher,as the projectiles reach it substantially simultaneously. Launching oneprojectile at a time may result in the animal fleeing, making itdifficult to track down the same animal and administer a second (ordifferent) dose.

Similarly, it may be necessary to treat an animal with a combination ofbiologically active agents. This may be accomplished by using aprojectile having contained therein a combination of biologically activeagents. However, it is not always possible to produce a projectilehaving two or more different biologically active agents therein, due toadverse reactions occurring between such biologically active agents whenthey are co-mixed. However, in some instances it may not be feasible toproduce a single projectile large enough to accommodate the requiredunitary doses of two or more biologically active agents. It may also beproblematic to launch such a large projectile at the animal withsufficient velocity to rupture the projectile upon impact, but not uponfiring.

Alternatively, a user may elect to launch two or more projectiles eachcontaining a different biologically active agent or different set ofbiologically active agents individually at the animal.

The launcher may be loaded with projectiles in a pre-determined serieswhich may be discharged substantially simultaneously, one may elect toload, say, a projectile containing a systemic anthelmintic, anotherprojectile containing an externally administrable insecticide and athird projectile containing a health supplement (each projectile havingdifferent, easily identifiable marker dyes included within theprojectile), pre-set the launch to launch three projectiles, andaccordingly treat an animal with the three biologically active agents,substantially simultaneously.

It follows thus that a user may elect to load the launcher with severalseries of such projectiles, following which each time the launcher isaimed at an animal and the trigger is pulled, a selected series ofprojectiles is discharged.

The invention extends thus to a method of loading a launcher of theinvention, by loading a plurality of such series of projectiles, eachcontaining a unit dosage of a biologically active agent, which may bethe same, or different.

Results

Projectile

A. Preparation of the Gelatine Base

The ingredients for projectile base were:

water, glycerine and/or sorbitol, and gelatine.

The glycerine and water were weighed in a suitable tank, temperatureregulated at about 65° C.

The gelatine was weighed in a separate tank.

The melting apparatus was under vacuum to load the glycerine and watersolution, then the vacuum was stopped and the solution was slowly mixed,heating at 80-85° C.

The gelatine was added under vacuum, keeping the blade stirrer atmaximum speed.

After 5 minutes of mixing, the vacuum was maintained to remove the airfrom the projectile base. The vacuum was stopped when there were no airbubbles in the projectile base.

The projectile base was ready to discharge in the gelatine tanks heatedat 60° C., applying a pressure with the nitrogen.

B. Preparation of the Fill

The contents of the projectile was either a solution or suspension.

Solution—The pre-weighed medicaments, additives and dissolving liquidsare put into a stainless steel “Vessel” and stirred until dissolutionwas completed. Vacuum was applied. The solution was typically at roomtemperature but preparations can be heated to form the requiredsolution.

Suspension—The suspending agents were weighted into an heated tank, andstirred during the addition of fats and waxes, that are added from aseparate tank where they are kept molten.

To the homogeneous liquid phase are added the powdered ingredients,adding first the more lighter components to avoid a rapid sedimentation.

The mixture was passed through a colloid mill to homogenise the system,and to reduce the particle size of raw materials. Then, the preparedsuspension was de-aired by the vacuum, because the presence of air cancause dosage variation at the filling site, since the dosing pumpdelivers a constant volume.The material was then transferred to a tank.C. Projectile Manufacture and Filling

The soft gelatine projectile was filled with the composition to form theprojectile. This was achieved by feeding two ribbons of gelatine betweentwo die-rolls, into the nip of which the liquid contents of theprojectile are fed.

Matching pockets on the rolls allow the fill to distend the gelatineribbon and mould it to a fixed shape. Simultaneously the edges of theformed projectile are welded together.

The gelatine ribbon is formed in the body of the machine itself.Projectile base from the supply tank flows down by gravity through acleanline pump and heated tubes to a spreader box. The spreader boxessit upon a rotating casting drum. The back face of the spreader box(gate) can be raised by a pair of screws so that the width of the slotat the gate of the box, through which the gelatine passes, can beincreased or decreased. It is possible to maintain a uniform machineoutput by changing the film thickness to compensate the changes of thegelatine.

The gelatine structure can be modified:

-   -   by temperature    -   by age    -   by viscosity    -   by elasticity (bloom)

The projectile base, when spread onto the casting drums, travels roundthe periphery over a period of about a minute, cooling and setting as itgoes. The drums are cooled by a flow of air coming from the coolingsystem situated on the back of the machine.

The ribbon is then picked off by a roller and passes between a pair oflubrification rollers, that give the lubrification with a vegetable oil(MIGLYOL) to both sides of the ribbon. Now the two ribbons are ready forthe passage through the filling section of the machine.

Two such ribbons are formed at the same time, and pass over the feederrolls onto the pockets of the die-rolls. As the opposing cavities cometowards one another, a unit dose of the contents is injected by onestroke of a double-acting piston pump. The contents reach the cavitiesthrough holes drilled in a metal block, the injection segment, whichrides under its own weight on the gelatine ribbons entering to thepockets.

The segment surfaces are curved to conform to the roll configuration. Asthe gelatine ribbon passes the segment, it receives the liquid,deforming into the cavities to accept it.

The edges of the projectile are then sealed, welded evenly by the rollpressure and are cut off all around as the projectile passes between thenarrowest part of the inter-roll gap. Below the rolls, the projectilesfall freely into twin belt conveyors, whilst the net continues to travelvertically downwards.

D. Drying Process

The drying of the projectiles is divided in two phases:

-   -   in a tumble dryer    -   in a drying tunnel.

The first phase, which occurs in the tumble dryers, is the relativelyrapid removal of the water that is going to be removed.

The rate-limiting factors are mainly:

-   -   the boundary layer in the air film surrounding the projectiles,        which can be reduced in thickness by increasing the ventilating        air rate;    -   the second is depending of the rate at which water can diffuse        through the gelatine of the projectile, and this is a function        of:    -   temperature    -   amount of plasticiser in the gelatine    -   nature of the fill.

The projectiles are finish-dried therefore in a drying tunnel, where airis supplied at

a relative humidity of below about 20%, and a temperature of about 22 to24° C.

Normally the projectiles are held for about 2 to 5 days in such anenvironment to reduce the moisture content of the gelatine to about 6 to12%.

For projectile contents containing water-soluble vehicles, the dryingtime is usually extended because the contents may have adsorbed waterfrom the shell and will release it only slowly.

The rate of drying is typically matched to the slowest diffusionrate-process in the system, otherwise the projectile may fail duringdrying, or will re-equilibrate on storage.

E. Inspection

After the final drying, ideally every projectile should undergoinspection. The principal defects are selected from critical defects(foreign projectiles, leaking projectiles, under or over weightprojectiles) and major & minor defects (mis-shapes, air bubbles, colourand clarity, greasiness, twins).

A first inspection can be carried out on the drying trays, where theleaking projectiles are easily removed and where possible to check forthe other defects.

A second Inspection can also be carried out automatically by means of ariddling machine (PHARMASORT 6-12, for example). Automatic inspection,however, will only eliminate projectiles being under or over weight,twins or mis-shaped.

F. Packaging

Normally projectiles made by the manufacturer are packed in standardbulk packs, the number of projectiles per pack depending upon the sizeof the projectile. The projectiles can be counted by either electronicor weight counters. The electronic counter, while giving precise count(deviation less than 0.2%), tends to be very slow. The weight counterhas a speed of more than 500,000 projectiles/hours. The projectiles arethen put into standard 0.125 mm polythene bags and heatsealed, and thenpacked in corrugated cardboard cartons, which are placed on pallets.

This package will protect the projectiles for between three and sixmonths from excessive moisture pick up, if stored under normal warehouseconditions.

Formulation and Trials Service

Phase 1

-   -   I. Laboratory trials on the received Customer fill material.        Check encapsulation suitability.    -   II. Definition of quali-quantitavive draft master formula (fill        and shell).    -   III. First encapsulation trial, typically with minimum 5 litres        of fill preparation.    -   IV. Preliminary stability test.    -   V. Points I-IV allow the generation of a preliminary master        formula.        Phase 2        Preparation of Final Master Formula.    -   VI. Master formula must be verified with a pilot trials of        maximum 20 litres of fill each.    -   VII. Final trial to set up the product.    -   VIII. Stability test.        Suitable Formulations

The tables below illustrate a number of examples of tested and trialformulations, including those with added transdermal enhancers designedto improve systemic take up of active pharmaceutical in a variety ofconcentrations, examples being propylene glycol (PG) and N-methyl-2pyrrolidone (NMP).

Formulation 1—Iver 30

Ingredient g/l Descriptor Approx % v/v Ivermectine 30.0 Active  3%N-propyl gallate Stabiliser Minor Thiodipropionic acid Stabiliser MinorRed DC 133 Dye Minor 1-methoxy 2-propanol (glysolv Minor solvent 10%PM/Icinol PM) Ethylene glycol monobytylether Minor solvent 10-20% (butylglysolv/butyl icinol) Butyl di-glysolv (butyl-icinol) Major solvent35-50%Formulation 2—Iver 15

Ingredient g/l Descriptor Approx % v/v Ivermectine 15.0 Active  3%N-propyl gallate Stabiliser Minor Thiodipropionic acid Stabiliser MinorRed DC 133 Dye Minor 1-methoxy 2-propanol (glysolv Minor solvent 10%PM/Icinol PM) Transcutol Minor solvent 10-20% Butyl di-glysolv(butyl-icinol) Major solvent 35-50% Azone 1-5%Formulation 3—Abamectin 30

Ingredient g/l Descriptor Approx % v/v Abamectin 30.0 Active  3%N-propyl gallate Stabiliser Minor Thiodipropionic acid Stabiliser MinorRed DC 133 Dye Minor 1-methoxy 2-propanol (glysolv Minor solvent 10%PM/Icinol PM) Transcutol Minor solvent 10-20% PG Major solvent 35-50%Azone 1-5%Formulation 4—Abamectin 5

Ingredient g/l Descriptor Approx % v/v Abamectin 5.0 Active  3% N-propylgallate Stabiliser Minor Thiodipropionic acid Stabiliser Minor Red DC133 Dye Minor 1-methoxy 2-propanol (glysolv Minor solvent 10% PM/IcinolPM) Transcutol Minor solvent 10-20% NMP Major solvent 35-50%Formulation 5—Iver 20

Ingredient g/l Descriptor Approx % v/v Ivermectine 20.0 Active  3%N-propyl gallate Stabiliser Minor Thiodipropionic acid Stabiliser MinorRed DC 133 Dye Minor 1-methoxy 2-propanol (glysolv Minor solvent 10%PM/Icinol PM) Transcutol Minor solvent 10-20% PG Major solvent 35-50%NMP 10%Formulation 6—Iver 30 plus

Ingredient g/l Descriptor Approx % v/v Ivermectine 30.0 Active  3%N-propyl gallate Stabiliser Minor Thiodipropionic acid Stabiliser MinorRed DC 133 Dye Minor 1-methoxy 2-propanol (glysolv Minor solvent 10%PM/Icinol PM) Transcutol Minor solvent 10-20% PG Major solvent 35-50%Azone 1-5%

Animal Trial Protocols Example 1 Protocol

The present inventors have developed a remote delivery new system (knownas the VetCap® Treatment System) for applying treatments such asanthelmintics to wild or unrestrained animals. The system, in apreferred form, comprises a gelatine-based projectile containing aspecially formulated anthelmintic, which is fired at animals with acompressed air “launcher” and it ruptures on impact and discharges theanthelmintic onto the skin of the animal.

VetCap® is a registered trade mark of Veterinary EncapsulationBioscience Pty Ltd used in relation to projectiles and methods oftreatment.

The system has been adapted for use in Africa for treating antelopespecies. Each projectile was designed to treat a 100 kg animal. Drugtrials in antelope species and cattle have been carried out in Africaand show that absorption of the active (abamectin) applied in aprojectile at the dosage rate of 5 g/l is at least as good as with atraditional Pour On application.

The system is adaptable for use in other animals such deer and cattle.

Formulations for the treatment of animals up to 600 kg in a singledosage projectile can be developed and evaluated, and a series of trialsis in progress to determine optimum formulation parameters for thispurpose.

Trial Requirements:

Compare the transdermal uptake of a formulation of the Iver 30(Ivermectin 30 g/l i.e. one projectile treats a 600 kg animal) andIver15 (Ivermectin 15 g/l i.e. one projectile treats a 300 kg animal)applied using a pour on method, with the same dosages applied with aprojectile containing the same endectocide. Blood sampling at intervalsafter treatment and a pharmacokinetic study show the plasma levels ofthe endectocide are substantially the same (i.e. bio-equivalence) intreated cattle.

Number of Animals Per Group:

Protocols for studies on anthelmintics in domestic animals usuallyspecify a minimum of six animals per treatment group. However, in apharmacokinetic study, if there are wide variations in plasma levels ofthe bioactive substance, this may not show statistically significant“bioequivalence”. Trials with pour-on formulations in cattle often showgreat variability, but this appears to be largely because cattle treatedwith pour on often lick themselves and each other, leading to plasmalevels resulting from oral as well as transcutaneous absorption.

Because this is only a “proof of concept” trial, n=3 was sufficient toshow substantially similar absorption from the projectile according tothe present invention compared with pour on treatment i.e. total numberof cattle was 12.

Group A (3 cattle): 10 ml Ivermectin formulation poured on to thesurface of the skin (30 g/l) to treat up to 600 kg animal.

Group B (3 cattle): One 10 ml projectile containing Ivermectin (30 g/l)to treat up to 600 kg applied using the system according to the presentinvention.

Group C (3 cattle): 10 ml Ivermectin formulation poured on to thesurface of the skin (15 g/l) to treat up to 300 kg

Group D (3 cattle): One 10 ml projectile containing the Ivermectin (15g/l) to treat up to 300 kg applied using the treatment system accordingto the present invention.

Pour-on doses to be drawn from existing VetCap® Iver 30 and Iver 15projectiles using a syringe, the needle is then to be removed andcontents ejected directly onto each animal in a single location(preferably in an approximately 20 centimetre circular patch on theupper flank of the animal in a similar area to where the animal will beshot with the projectile).

VetCap® projectiles to be fired from 15 metres at the flank of eachanimal to be treated. If the projectile misses the animal, the treatmentis to be repeated. If there is a partial “hit”, then the animal will bediscarded from the group and replaced by another equivalent animal thatis then treated fully.

Pharmacokinetic Study

Prior to analysis of the blood samples, one Iver30 projectile and oneIver15 projectile from the same batch as that used to for the fieldtrial was tested by the laboratory to ensure that the Ivermectin levelspresent in the formulation were stable at 30 g/l and 15 g/lrespectively. Once confirmed the laboratory tested the blood samples.

Blood sampling (2×10 ml “green top” heparinised blood sample):

Sample all groups (A, B, C, D) on days 0, 1, 2, 3, 4.

Blood samples were spun down as soon as possible, serum extracted andafter collection and the duplicate plasma samples frozen at −20 C. Atthe completion of the trial, one set of samples was sent to theanalytical testing laboratory for assaying for Ivermectin. The duplicateset was retained until the first set had been analysed and resultsassessed, in case the samples are lost in transit or there is any needto repeat the analyses.

Pretrial:

Ensure all animals are healthy.

Ensure that no anthelmintic is given in 8 weeks prior to trial starting.

Ensure all animals have individual eartags

Ensure yarding systems are adequate and there is adequate provision forfeed throughout the 6 week trial

Trial Schedule:

Day-7 Check equipment, test ballistics, target practice, measure impactetc

Day-7 Check Cattle, health, tags, weigh, allocate to groups

Day 0 Blood sample Groups (A, B, C, D) weigh, treat groups

Day 1 Blood sample Groups (A, B, C, D)

Day 2 Blood sample Groups (A, B, C, D)

Day 3 Blood sample Groups (A, B, C, D)

Day 4 Blood sample Groups (A, B, C, D)

Day 7 Blood sample, Groups (A, B, C, D)

Day 14 Blood sample, Groups (A, B, C, D)

Day 28 Blood sample, Groups (A, B, C, D)

Day 35 Blood sample, Groups (A, B, C, D)

Day 42 Blood sample, Groups (A, B, C, D)

Trial ends and animals remained at the research facility for a minimumof 5 weeks before resale or slaughter (WHP 35 days).

Results confirmed preliminary work that the system according to thepresent invention provided desired levels of treatment.

Trial Data

The following independent trials were conducted at the South AfricanAgricultural Research Council establishment at Irene, Pretoria under thedirection of the SA Registrar of Veterinary Medicines and in accordancewith product registration procedures:

The purpose of the trial was to establish the efficacy of biologicallyactive agent when administered by the system according to the presentinvention in treating cattle for the endo-parasite wireworm.

Two cattle of similar age and weight (˜200 kg) were infected withwireworm parasite to the level of 6000 to 8000 worm eggs per gram offaeces. One cow was treated with the biologically active agent in its‘pour on’ form and the other cattle were treated with two dosageprojectiles fired from a distance of approx 20 metres with a CO₂propelled launcher with an impact velocity of about 130 ft/sec.

Each projectile was spherical and made from soft gelatine compound withthe shell being of about 2 mm thick. The size was sufficient to holdabout 10 ml of the liquid biologically active agent comprising thefollowing constituent:

10 mg of abamectin (at a dosage concentration of 1 mg per 10 kg of bodymass)

5% solution of the solvent/transdermal carrier propylene glycol (theproprietary brand Icinol)

a standard turquoise, inert pharmaceutical colorant known as FC & D blue

The impact area of the ruptured projectiles was the hind quarter andlower neck/shoulder of the cattle.

The cattle were slaughtered 3 weeks after treatment and the stomachcontents/linings examined under laboratory conditions. The cow treatedby projectile administration was found to be 100% free of internalparasite infection—the other treated cow was approx 96% free ofparasite.

This test showed that the treatment method according to the presentinvention met with industry efficacy standards for treatment ofendo-parasites when used in conjunction with the transdermalformulation.

The enhanced efficacy of the projectile method of administration in thistest may be attributable directly to the delivery method. This involvedsubcutaneous bruising around the impact site. This caused dilation ofthe blood vessels and it is postulated that this reaction enhances thetreatment efficacy through better absorption of the pharmaceuticalingredients into the blood stream.

Further independent trials were carried out in South Africasubstantially in accordance with the above stated protocol on 6 cattle.The research objective of this trial was to determine the extent (ifany) to which administration of pure (non-solubilised) ivermectin by themethods contemplated by the present invention were effective to treatparasite disease in cattle.

The subject cattle were treated with external delivery ofnon-solubilised ivermectin in soya oil suspension fluid (containing noknown solvent or other transdermal carrier agent) within a standardgelatin projectile as described. The ivermectin content was theequivalent of the standard 5 gram per litre ‘pour on’ solutions.

Blood test analysis revealed no significant systemic take up of theivermectin, and effective therapeutic blood level was not achieved. Thistrial confirmed the accepted scientific opinion of those practised inthe art—namely, that the external administration of non-solubilisedivermectin is ineffective for therapeutic treatment purposes.

Example 2 Look and See Trial of VetCap® Projectile on 2 Bos TaurusWeaner Calves

The purpose of the trial was to determine the efficacy against ticks ofa formulation containing 0.5% solubilised abamectin and transdermalsolvent encapsulated inside a gelatine projectile (with each boluscontaining 10 ml of the composition) applied externally onto the calvesby means of a specially designed compressed airgun, similar to a dartgun or paintball marker termed a VetCap® ‘launcher’. Efficacy of thetest article against ticks on calves was assessed for registrationpurposes in South Africa. The test active was applied at a dose rate ofa 10 ml bolus/100 kg body weight and animals were observed and tickscounts done before treatment and again after 7 days.

The test active was applied at a rate of one 10 ml VetCap® projectile(VetCap®) for animals weighing up to 100 kg and two 10 ml VetCaps foranimals weighing between 100 to 200 kg. The projectiles containing thetest active were loaded into the VetCap® launcher and shot at the animalto be treated from a distance of about 2 m.

Tick counts were done on day 0, before treatment; and on day 7 aftertreatment according to the applicable standard operating procedure.Ticks were counted and identified in situ. In each case ticks on thewhole animal were counted. No adverse reactions to the test activeoccurred. The percentage efficacy of VetCap® applied as a ballisticbolus, against adult Boophilus, was 92.7%. Percentage efficacy againstimmature Boophilus was 98.6%.

Example 3 VetCap® Tolerance in Sheep and Goats

The purpose of this trial was to determine the safety of an abamectinformulation applied using the VetCap® treatment system (Ballistic Boli)in sheep and goats. The formulation containing 0.5% solubilisedabamectin and transdermal solvent was encapsulated inside a gelatineprojectile with each bolus containing 10 ml of the compound. Theformulation may cause adverse symptoms in animals and safety had to beassessed for registration purposes in South Africa. Ten healthy sheepand 10 healthy goats were treated with the test article. As all theanimals were treated, no provision for ranking, allocation toexperimental groups and statistical procedures was required. The testarticle was applied at a rate of one 10 ml bolus for animals weighing upto 100 kg and two 10 ml boli for animals weighing between 100 to 200 kg.The VetCap® boli containing the test active were loaded into a speciallydesigned compressed air rifle (VetCap® ‘launcher’) and shot at theanimal to be treated from a distance of about 2 m as set out in thetable below:

Criteria to be assessed are shown in the table below. The scoring was asfollows:

0=Normal; 1=Mild; 2=Moderate; 3=Severe; 4=Extremely severe

No adverse symptoms or reactions to the test active were observed in anyof the animals during the trial. The test active would therefore beregarded as safe for use in the trial animals, when administered usingthe VetCap® treatment system administration method in ballistic bolusform.

Example 4 Histological Impact Study of VetCap® in Ovine, Caprine andBovine

The objective of this study was to determine the histological impact ofan abamectin formulation in ovine, caprine and bovine. The formulationcontaining 0.5% solubilised abamectin and transdermal solvent wasencapsulated inside a gelatine projectile with each bolus containing 10ml of the compound. The bolus can be shot onto the body of an animal byusing a specially designed compressed air rifle, similar in operation toa dart gun or paintball marker (VetCap® launcher).

Histological evaluation of skin, subcutis and muscle specimens, fromsites of bolus impact, was done. Twelve animals were involved in thetrial, four of each species. The boli were applied to two animals ofeach species from a distance of 1 m at a dose rate of 1 bolus per animaland to the other two animals of each species from a distance of 5 m atthe same dose rate, The breeds involved in the study were Dorper HairSheep, indigenous goats and Nguni cattle calves.

The experimental lay-out and sampling schedule is shown in the followingtables.

The sheep were shorn before application of the boli, but not the goatsand calves, as their hair was unlikely to lessen the impact of the boli.Twenty-four hours after treatment, two animals from each species, oneshot from a distance of 1 m and the other shot from a distance of 5 m,were necropsied and biopsies taken. One sample was taken from eachanimal and placed in formalin. The same schedule was followed 48 hoursafter treatment. Samples were taken to pathologist after completion ofthe animal phase.

TABLE 1 Histological evaluation of ovine samples: Time interval AnimalSample Shooting after number number distance treatment Sample typeHistological evaluation 2C A 5 m 24 h Skin Histologically normalSubcutaneous Histologically normal tissue Skeletal One small focal arearevealed muscle a mild infiltration of lymphocytes in the interstitiumof the muscle tissue  C B 1 m 24 h Skin Histologically normalSubcutaneous Histologically normal tissue Skeletal Two small focal areasof muscle mainly lymphocytic infiltration of a very mild nature in theinterstitial tissue between the muscle fibres 2D C 5 m 48 h SkinHistologically normal Subcutaneous Not present tissue SkeletalHistologically normal muscle  D D 1 m 48 h Skin Mild peri vascularinfiltration of lymphocytes and plasma cells in the superficial dermisSubcutaneous Multifocal nodular areas tissue revealed dense fibroblasticproliferation with larger numbers of lymphocytes, plasma cells andmacrophages associated with the reaction. Moderate numbers oflymphocytes and plasma cells were present perivascularly in these areas.Two of the areas contained foreign material compatible withplant/hair-type material Skeletal Histologically normal muscle

TABLE 2 Histological evaluation of caprine samples: Time interval AnimalSample Shooting after number number distance treatment Sample typeHistological evaluation 2A F 5 m 24 h Skin A focal area of the skinsection revealed a moderate perivascular lymphoplasmacytic infiltrationin the superficial dermis. There is moderately increased amounts ofcollagen in the superficial dermis. Subcutaneous Histologically normaltissue Skeletal Histologically normal muscle  A E 1 m 24 h Skin Mildlyincreased amounts of fibroblasts and collagen in the superficial dermisSubcutaneous Histologically normal tissue Skeletal Histologically normalmuscle 2B H 5 m 48 h Skin Moderate perivascular lymphoplasmacyticinfiltrations were evident in superficial blood vessels of the dermis.Moderate to severe orthokeratotic hyperketosis was also evidence in theskin section as well as moderate increase in superficial dermal collagenSubcutaneous Histologically normal tissue Skeletal Histologically normalmuscle  B G 1 m 48 h Skin A moderate lymphoplasmacytic perivascularinfiltration was visible in the superficial dermis of the skin section.Severe orthokeratotic hyperkeratosis was also evident and moderateincrease in superficial dermal collagen Subcutaneous Histologicallynormal tissue Skeletal Histologically normal muscle

TABLE 3 Histological evaluation of bovine samples: Time interval AnimalSample Shooting after number number distance treatment Sample typeHistological evaluation 2E J 5 m 24 h Skin Mild perivascularlymphoplasmacytic infiltrates were visible in the superficial dermisSubcutaneous Histologically normal tissue Skeletal Histologically normalmuscle  E I 1 m 24 h Skin A moderate perivascular infiltration of mastcells and eosinophills were visible in around the superficial bloodvessels of the dermis Subcutaneous Histologically normal tissue SkeletalHistologically normal muscle 2F L 5 m 48 h Skin Mild perivascularinfiltrations of lymphoplasmacytic, plasma cells as well as a smallnumber of neutrophils were evident in the dermis SubcutaneousHistologically normal tissue Skeletal Histologically normal muscle  F K1 m 48 h Skin Moderate numbers of lymphocytes, plasma cells as well aseosinophils and few mast cells were evident perivascularly surroundingthe superficial blood vessels of the dermis Subcutaneous Histologicallynormal tissue Skeletal One small focal area revealed muscle a mainlylymphocytic infiltration in the interstitial tissue

The above results indicate no serious injury or unacceptable levels oftissue damage caused to any of the test subjects. The method of deliveryusing the VetCap® treatment system according to the present inventionwas therefore deemed safe under the test conditions.

Example 5 The Remote Treatment of Ticks on Nguni-Cross Calves (Bostaurus & Bos indicus Traits) with VetCap®

The purpose of the trial was to determine the efficacy against ticks ofa 0.5% (m/v) abamectin formulation applied topically in calves by meansof a specially designed compressed airgun (VetCap® launcher). Aformulation containing solubilised abamectin and transdermal carrierswas encapsulated in a bolus with a gelatine projectile, containing 10 mlabamectin, which was shot onto the body of the test animals by means ofa the VetCap® launcher. Efficacy of the test active against ticks oncalves was assessed for registration purposes in South Africa. The testactive was applied at a dose rate of a 10 ml bolus/100 kg body weightand animals were observed and ticks counts done before treatment andagain after 7 days.

Administration of the test active took place according to the table. Thetest active was applied at a rate of one 10 ml bolus for animalsweighing up to 100 kg and two 10 ml boll for animals weighing between100 to 200 kg. The boli containing the test active were loaded into theVetCap® launcher and shot at the animal to be treated from a distance ofabout 12 m.

Example 6 Degradation of VetCap® Containing Abamectin in the Environment

An antiparasitic formulation containing solubilised abamectin andtransdermal carriers was encapsulated in a bolus with a gelatineprojectile, containing 10 ml abamectin. The detailed descriptions areshown in Table 4. Discolouration took place, especially in the sun(faster and more pronounced). The broken boli shrivelled anddeteriorated fast, especially the one in the sun. Both the whole andunbroken boli in the sun showed faster discolouration and deteriorationwhen compared to the ones placed in the shade. Leakage of content wasobserved after 21 days in the whole bolus placed in the sun and at 28days in the whole bolus placed in the shade. The process wasphotographed and recorded. Degradation of the VetCap® projectile led toonly pieces of shell being present after 28 days in all the cases,whether left in the sun or shade and therefore this is determined as itsmaximum exposure limit.

TABLE 4 Degradation of projectile Observations of the whole VetCap ®bolus Placement Day 0 Day 7 Day 14 Day 21 Day 28 Shade Blue Blue BlueBlue Blue Unbroken Unbroken Unbroken Unbroken Leakage Diameter DentedLarger dent Larger dent occurred ±3 cm No leakage No leakage No leakageLarger dent Diameter Diameter Diameter Diameter ±3 cm ±3 cm ±3 cm ±2 cmSun Blue White White White White Unbroken discolouration discolourationdiscolouration discolouration Diameter Diameter Large dents LeakageShrivelled ±3 cm ±3 cm No leakage Diameter Diameter ±2.6 cm ±2 cm ShadeLight blue Light blue Whitish Whitish Small pieces discolourationdiscolouration discolouration discolouration of shell Empty Shell brokenShell broken Shell broken Transparent and shrivelled into smaller intosmaller white pieces pieces Sun Light blue Broken Broken Broken Brownishdiscolouration pieces of pieces of pieces of pieces of Empty shell shellshell shell Transparent Transparent Transparent white white white

Example 7 The Efficacy of VetCap® Against the Nematode Parasites ofBlesbuck

The game farming industry is in need of registered anthelmintics forgame animals, but for the registration of an anthelmintic it is requiredby the registering authorities that the efficacy of such an anthelminticbe validated in the target animal species before it can be registered. Aprevious efficacy study was done with a medicated food additive inimpala, but great difficulty was experienced in getting the wild animalto take medicated feed, therefore it was decided to attempt analternative method of applying abamectin in order to combat parasiticchallenge.

A specially prepared antiparasitic formulation containing solubilisedabamectin and transdermal carriers was encapsulated in a bolus with agelatine projectile, containing 10 ml abamectin, which was shot onto thebody of the test animals by means of a specially designed compressed airrifle (VetCap® launcher). The objective of the study was to determinethe anthelmintic efficacy of the abamectin formulation delivered usingthe treatment system according to the present invention against thenematode parasites of blesbuck.

The abamectin formulations in the projectiles were applied to 6 blesbuckat a rate of 1 bolus/10 ml per kg, while a further 6 blesbuck were keptuntreated as control. The blesbuck were slaughtered and the nematodeparasites in the abomasums recovered, counted and compared to calculatethe effect of the abamectin formulation applied using the test system.On day 7 after treatment, the animals in groups 1 and 2 were slaughteredand the abomasums collected and processed to recover nematode parasites.Only abomasal parasites were recovered in the treated animals and thebolus formulation was 98.37% effective against the Haemonchus spp.present. The high efficacy rating is an indication of the potential ofthis form of treatment for game animals is illustrated Table 5 below.

TABLE 5 Efficacy of projectile Experimental Haemonchus spp. recoveredGroup Animal Number Immature Adult Total Group 2 2 20 205 225 Untreated4 45 170 215 Control 6 15 205 220 8 0 40 40 10 115 240 355 12 50 125 175Geometric Mean 172.79 group 1 1 0 5 5 Virbamax 3 0 20 20 Ballistic Ball5 0 0 0 7 0 0 0 9 5 0 5 11 0 0 0 Geometric Mean 2.82 AnthelminticEfficacy % 98.37

It will be appreciated by persons skilled in the art that numerousvariations and/or modifications may be made to the invention as shown inthe specific embodiments without departing from the spirit or scope ofthe invention as broadly described. The present embodiments are,therefore, to be considered in all respects as illustrative and notrestrictive.

The invention claimed is:
 1. A remote treatment delivery system for ananimal comprising: a dosage projectile adapted to deliver a biologicallyactive agent to the animal substantially without piercing the skin ofthe animal and containing a biologically active agent and a transdermalcarrier in liquid or gel form, wherein the agent and the carrier areencapsulated in one or more encapsulating agents; and wherein theencapsulating agents forms a frangible shell.
 2. The delivery systemaccording to claim 1 wherein the biologically active agent is ananthelmintic, acaricide or an anti-parasitic composition or compound. 3.The delivery system according to claim 2 wherein the biologically activeagent is a macrocyclic lactone selected from the group consisting ofivermectin, abamectin, eprinomectin, moxidectin, selamectin, doramectin,and emamectin benzoate.
 4. The delivery system according to claim 2wherein the biologically active agent is a synthetic pyrethroid selectedfrom the group consisting of flumethrin, deltamethrin, cypermethrin,cyfluthrin, fenvalerate, alphacypermethrin and pyrethrin.
 5. Thedelivery system according to claim 2 wherein the biologically activeagent is an insect growth regulator selected from the group consistingof yriproxifen, methoprene, cyromazine, lufenuron, diflubenzuron,fluazuron, and dicyclanil.
 6. The delivery system according to claim 1,wherein the biologically active agent is an amidine.
 7. The deliverysystem according to claim 2, wherein the acaricide is anorganophosphorous acaricide.
 8. The delivery system according to claim2, wherein the biologically active agent is selected from the groupconsisting of fipronil, imidacloprid, rotenone, Mg flurosilicate,piperonyl butoxide, spinosyns, benzimidazoles and amino-acetonitrilederivatives.
 9. The delivery system according to claim 1, wherein thebiologically active agent is a hormone.
 10. The delivery systemaccording to claim 1, wherein the biologically active agent is ananti-infective, anaesthetic, analgesic, anti-inflammatory, antibiotic,anti-fungal, antihistamine, antiviral, antioxyltic, β-adrenergicagonist, bronchodilator, cardioactive, CNS stimulating, cholinergic,ant-cholinergic, anti-emetic, muscle-relaxing or antimicrobial agent.11. The delivery system according to claim 1, wherein the biologicallyactive agent is a health supplement.
 12. The delivery system accordingto claim 11, wherein the health supplement is a vitamin or mineral. 13.The delivery system according to claim 1, wherein the biologicallyactive agent is a vaccine or immunogenic compound.
 14. The deliverysystem according to claim 1, further comprising one or more adjuvants.15. The delivery system according to claim 1, wherein the transdermalcarrier is selected from the group consisting of isopropyl alcohol;dipropylene glycol methyl-ether; butylated hydroxytoluene dipropyleneglycol monomethyl-ether; methylene chloride; diethyl ether, ethanol,acetonitrile, ethyl acetate, benzyl alcohol and a combination of naturaloils, ethylene glycol, propylene glycol, dimethyl polysiloxane (DMPX),oleic acid, caprylic acid, 1-octanol, ethanol (denatured or anhydrous),liposomal compositions, plant oils, acrylic polymers, rubber-basedpolymers, polysiloxane-based polymers, polyvinylpyrrolidone-basedpolymers, dimethylsulfoxide (DMSO), dimethylformamide (DMF), lecithin,bi-component vesicular aggregates, ethosomes, azone, castor oilderivatives, jojoba oil derivatives, corn oil derivatives, and emu oilderivatives.
 16. The delivery system according to claim 15, wherein thetransdermal carrier is propylene glycol, DMSO, alcohol, or a penetrantadjuvant.
 17. The delivery system according to claim 1, furthercomprising a marker able to mark the skin, coat or fur of an animal. 18.The delivery system according to claim 17, wherein the marker is capableof marking the animal for a period of about 1 hour to about 72 hours.19. The delivery system according to claim 18, wherein the marker marksthe animal for a period of about 24 to 48 hours.
 20. The delivery systemaccording to claim 17, wherein the marker is a cosmetic colorant,pigment, or dye.
 21. The delivery system according to claim 20, whereinthe marker is a liquid dye, powder dye, water soluble dye, infra-reddye, ultraviolet dye, or a dye that glows in the dark.
 22. The deliverysystem according to claim 1, wherein the frangible shell is made ofgelatine, linear polymers, or polystyrene derivatives, thin-walledplastics materials, hydrophilic colloidal materials including gelatin,albumin, gum arabic, alginate, casein, agar or pectins, syntheticorganic compounds, resinous compounds, or combinations thereof.
 23. Thedelivery system according to claim 15 wherein the plant oil is selectedfrom the group consisting of Aloe vera oil, sesame seed oil, andderivatives thereof.
 24. The delivery system according to claim 15wherein the castor oil derivative is ethoxylated castor oil.
 25. Thedelivery system according to claim 1, wherein the animal is a wildlifeor game animal, a livestock animal, or a feral animal.
 26. The deliverysystem according to claim 25, wherein the wildlife or game animal isselected from deer and buffalo.
 27. The delivery system according toclaim 25, wherein the livestock animal is selected from the groupconsisting of cattle, pigs, goats, sheep, and horses.
 28. The deliverysystem according to claim 25, wherein the feral animal is selected fromthe group consisting of dogs, goats, and pigs.